Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells
Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells
复制标题
DOI：
10.1210/en.2002-220620
复制
发表时间：
2003-03-01
期刊：
影响因子：
4.8
通讯作者：
Nicholson, RI
中科院分区：
文献类型：
--
作者：
Knowlden, JM;Hutcheson, IR;Nicholson, RI
抗激素药物获得性耐药的发展是乳腺癌治疗中的一个主要问题。我们已经开发了一种他莫昔芬耐药（TAM-R）MCF-7乳腺癌细胞系，以研究这种情况背后的机制。与野生型MCF-7细胞相比，TAM-R中表皮生长因子受体（EGFR）和c-erbB 2 mRNA和蛋白表达均增加，而两种细胞系中c-erbB 3 mRNA和蛋白表达水平相当。在基础条件下，磷酸化EGFR/c-erbB 2，EGFR/c-erbB 3，但不是c-erbB 2/c-erbB 3受体异源二聚体检测TAM-R细胞与磷酸化细胞外信号调节激酶1/2（ERK 1/2）的水平增加。两种细胞系都能够产生一系列EGFR特异性配体，并且在TAM-R细胞中观察到转化生长因子a表达增加。用ZD 1839（易瑞沙）或曲妥珠单抗（赫赛汀）处理TAM-R细胞可阻断c-erbB受体异源二聚体的形成和磷酸化，降低ERK 1/2活性，并强烈抑制细胞生长。MAPK激酶抑制剂PD 098059特异性降低磷酸化ERK 1/2水平并抑制TAM-R生长。所有这三种药物都消除了野生型细胞中的ERK 1/2活性，但仅引起细胞增殖的小幅减少。这些结果表明，TAM-R MCF-7细胞生长是由EGFR特异性配体的自分泌释放和作用介导的，该配体诱导优先EGFR/c-erbB 2二聚化和ERK途径的下游活化。
The development of acquired resistance to antihormonal agents in breast cancer is a major therapeutic problem. We have developed a tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line to investigate the mechanisms behind this condition. Both epidermal growth factor receptor (EGFR) and c-erbB2 mRNA and protein expression were increased in TAM-R compared with wild-type MCF-7 cells, whereas comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. Under basal conditions, phosphorylated EGFR/c-erbB2, EGFR/c-erbB3 but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased levels of phosphorylated extracellular-signal regulated kinase 1/2 (ERK1/2). Both cell lines were capable of generating a range of EGFR-specific ligands and increased expression of transforming growth factor a was observed in TAM-R cells. Treatment of TAM-R cells with ZD1839 (Iressa) or trastuzumab (Herceptin) blocked c-erbB receptor heterodimer formation and phosphorylation, reduced ERK1/2 activity, and strongly inhibited cell growth. The MAPK kinase inhibitor PD098059 specifically reduced phosphorylated ERK1/2 levels and inhibited TAM-R growth. All three agents abolished ERK1/2 activity in wild-type cells but caused only small reductions in cell proliferation. These results demonstrate that TAM-R MCF-7 cell growth is mediated by the autocrine release and action of an EGFR-specific ligand inducing preferential EGFR/c-erbB2 dimerization and downstream activation of the ERK pathway.